This invention in the field of immunology, more particularly the therapeutic use of superantigens.
The immune system plays a central role in both preventing and causing many diseases. It is of interest to provide methods and compositions for the induction of immune response directed against harmful cells and viruses. Similarly, it is of interest to provide methods and compositions to inhibit unwanted immune responses in autoimmune diseases such as rheumatoid arthritis or transplanted organ rejection. Superantigens, such as some bacterial enterotoxins, have been found to have profound effects on the proliferation of T cell populations. The invention described herein relates to methods and compositions for using superantigens to exert desirable therapeutic effects on the immune system.
Many superantigens are bacterial enterotoxins. The staphylococcal enterotoxins comprise a family low molecular weight proteins which share common physico-chemical properties. They are the most potent T-cell mitogens known being capable of activating a resting T-cell population in concentrations of 10xe2x88x9213 molar. Compared to a conventional antigen which may activate 1/3000 T-cells, enterotoxins may evoke proliferation in up to 30% of a resting T-cell population. The enterotoxins are members of a group of proteins known as superantigens which share the common property of binding to T-cell Vxcex2 receptors without the need for additional diversity elements resulting in massive lymphoproliferation, cytotoxic T-cell generation and lymphokine secretion (Bergdoll, M. S., Academic Press, London. (1983), Marrack, P., et al., Science, 248:750, (1990), Kotzin, B. L., et al., Advances in Immunology, 54:99, (1993), Drake, C.G., et al., J. Clinical Immunology, 18:12, (1992), Herman, A., et al., Annu. Rev. Immunol. 9:745, (1993), Scherer, M. T., et al., Annu. Rev. Cell Biology, 9:101-28, (1993), Terman, D. S., Cancer Research Institute, New York, N.Y., June (1993)).
Recent studies have shown that several enterotoxins are capable of inducing antitumor effects against established rodent melanoma, sarcoma and carcinoma when given parenterally Mokyr, M. B., et al., J Immunol., 151:4838, (1993), Weiner, G. J., et al., J. Immunol., 152:2385, (1994), Wallgren, A., et al., Blood, 31:1230 (1993), Rubin, M., et al., J. Immunol., 152:3522, (1994), Lando, P. A., et al., Cancer Immunol. Immunother., 33:231, (1991), Dohlsten, M., et al., Immunology, 97:520, (1993), Dohlsten, M., et al., Proc. Nat. Acad. Sci. USA, 88:9287, (1991), Dohlsten, M., et al., Proc. Nat. Acad. Sci., 91:8945, (1994), Dohlsten, M., et al., Int. J. Cancer, 54:482, (1993), Lando, P. A., et al., Cancer Immunol. Immunother., 36:223, (1993), Penna, C., et al., Cancer Research, 54:2738, (1994), Kalland, T., et al., Med. Oncol. and Tumor Pharmacother., 10:37, (1993), Newell, K. A., et al., Proc Nat""l. Acad. Sci. USA 88:1074 (1991), Ochi, A., et al., J. Immunol. 151:3180 (1993), Hedlund, G., et al., Cancer Immunol. Immunother. 36:89 (1993)).
In view of the numerous shortcomings with various currently available methods and compositions for the treatment of multiple neoplastic diseases, infectious disease, and autoimmune diseases, it of interest to provide new methods and compositions for the treatment of such diseases. The invention described herein relates to methods and compositions for using superantigens to exert desirable therapeutic effects on the immune system
The present invention relates to therapeutic methods and compositions employing superantigens. Methods and compositions employing superantigens and immunotherapeutic proteins in combination with one another have been found to provide more effective treatment than either component used alone. Superantigens, in conjunction with one or more additional immunotherapeutic antigens, may be used to either induce a therapeutic immune response directed against a target or to inhibit a disease causing immune response. Specific combinations of superantigens and immunotherapeutic antigens are used to treat specific diseases. The induction (or augmentation) of a desired immune response against a target may be used, for example, to kill cancer cells or kill the cells of an infectious agent. The inhibition of an immune response, e.g., through the induction of T cell anergy, may be used to reduce the symptoms of an autoimmune disease. Diseases that may be treated by the methods and compositions of the invention include neoplastic diseases, infectious diseases, and autoimmune diseases.
One aspect of the invention is to provide methods for the treatment of diseases comprising the steps of administering an effective amount of a superantigen and an immunotherapeutic so as to have the desired therapeutic effect. The superantigen and immunotherapeutic antigen may be administered together as a mixture. Alternatively, the superantigen and immunotherapeutic antigen may be administered separately. In one embodiment of the invention, the superantigen and immunotherapeutic antigen are administered to the patient in the form of a immunotherapeutic antigen-superantigen polymer of the invention.
Another aspect of the invention is to provide methods for the treatment of diseases comprising the steps of incubating a lymphocyte population ex vivo with a superantigen and an immunotherapeutic protein so as to either activate or anergize T cells within the selected population. The treated lymphocytes could then be introduced into a patient so as to have the desired therapeutic effect. The superantigen and immunotherapeutic antigen may be administered together as a mixture. Alternatively, the superantigen and immunotherapeutic antigen may be administered separately. In one embodiment of the invention, the superantigen and immunotherapeutic antigen are incubated with the lymphocyte population in the form of an immunotherapeutic antigen-superantigen polymer of the invention.
Another aspect of the invention is to provide immunotherapeutic antigen-superantigen polymers that comprise a first subunit that is a superantigen and a second subunit that is an immunotherapeutic antigen. The first and second subunits may be joined together either directly or indirectly through the use of crosslinking agents. The subunits may be joined together either covalently or non-covalently. The invention also provide methods of making a immunotherapeutic antigen-superantigen polymer useful for the treatment of various disease and immunotherapeutic antigen-superantigen polymers made by the subject methods; these methods involve the step of joining a superantigen and an immunotherapeutic protein to one another, especially through the use of crosslinking agents. In other embodiments of the invention, the immunotherapeutic antigen-superantigen polymers are recombinant chimeric proteins that comprise superantigen portions and immunotherapeutic antigen portions. Other embodiments of the invention include vectors and host cells for the recombinant production of the subject chimeric proteins.
Another aspect of the invention is to provide superantigen containing formulations for the treatment of neoplastic diseases, infectious diseases, and autoimmune diseases. The subject composition comprise either (I) a mixture of a superantigen and an immunotherapeutic antigen or (ii) a immunotherapeutic antigen-superantigen polymer of the invention. The subject formulations may further comprise carriers and excipients. The formulations of the invention may be adapted for a wide variety of methods of administration. In additional embodiments of the invention, the formulations may be encapsulated in liposomes.